title: Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.
abstract: We analyzed candidate platelet function disorder genes in 13 index cases with a history of excessive bleeding in association with a significant reduction in dense granule secretion and impaired aggregation to a panel of platelet agonists. Five of the index cases also had mild thrombocytopenia. Heterozygous alterations in FLI1 and RUNX1, encoding Friend leukemia integration 1 and RUNT-related transcription factor 1, respectively, which have a fundamental role in megakaryocytopoeisis, were identified in 6 patients, 4 of whom had mild thrombocytopenia. Two FLI1 alterations predicting p.Arg337Trp and p.Tyr343Cys substitutions in the FLI1 DNA-binding domain abolished transcriptional activity of FLI1. A 4-bp deletion in FLI1, and 2 splicing alterations and a nonsense variation in RUNX1, which were predicted to cause haploinsufficiency of either FLI1 or RUNX1, were also identified. Our findings suggest that alterations in FLI1 and RUNX1 may be common in patients with platelet dense granule secretion defects and mild thrombocytopenia.
authors.affiliation: Department of Cardiovascular Science, University of Sheffield Medical School, University of Sheffield, Sheffield, United Kingdom;
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stockley
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Lowe
authors.forename: Marie
authors.initials: M
authors.lastname: Lordkipanidzé
authors.forename: Ban
authors.initials: B
authors.lastname: Dawood
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Kirsty
authors.initials: K
authors.lastname: Macfarlane
authors.forename: Kevin
authors.initials: K
authors.lastname: Horner
authors.forename: Vincenzo C
authors.initials: VC
authors.lastname: Leo
authors.forename: Katherine
authors.initials: K
authors.lastname: Talks
authors.forename: Jayashree
authors.initials: J
authors.lastname: Motwani
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Wilde
authors.forename: Peter W
authors.initials: PW
authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Makris
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Martina E
authors.initials: ME
authors.lastname: Daly
mesh_terms: D001792:Blood Platelets; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005260:Female; D057895:Haploinsufficiency; D006470:Hemorrhage / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism; D055571:Secretory Pathway / Q000235:genetics*; D022142:Secretory Vesicles / Q000235:genetics* / Q000378:metabolism; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C078433:FLI1 protein, human; D051789:Proto-Oncogene Protein c-fli-1